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beta-site amyloid precursor protein cleaving enzyme 1 increases amyloid deposition in brain parenchyma but reduces cerebrovascular amyloid angiopathy in aging BACE x APP[V7171] double-transgenic mice

Record type: Article

The generation of amyloid peptides (Aß) from the amyloid precursor protein (APP) is initiated by ß-secretase (BACE), whereas subsequent {gamma}-secretase cleavage mediated by presenilin-1, produces Aß peptides mainly of 40 or 42 amino acids long. In addition, alternative ß'-cleavage of APP at position 11 of the amyloid sequence results in N-truncated Aß(11-40/42) peptides, but the functional significance or pathological impact is unknown. Here we demonstrate that in the brain of BACE x APP[V717I] double-transgenic mice, amyloidogenic processing at both Asp1 and Glu11 is increased resulting in more and different Aß species and APP C-terminal fragments. Pathologically, BACE significantly increased the number of diffuse and senile amyloid plaques in old double-transgenic mice. Unexpectedly, vascular amyloid deposition was dramatically lower in the same BACE x APP[V717I] double-transgenic mice, relative to sex- and age-matched APP[V717I] single-transgenic mice in the same genetic background. The tight inverse relation of vascular amyloid to the levels of the less soluble N-terminally truncated Aß peptides is consistent with the hypothesis that vascular amyloid deposition depends on drainage of excess tissue Aß. This provides biochemical evidence in vivo for the preferential contribution of N-truncated Aß to parenchymal amyloid deposition in contrast to vascular amyloid pathology.

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Citation

Willem, M., Dewachter, I., Smyth, N., Dooren, T., Borghgraef, P., Haass, C. and Leuven, F. (2004) beta-site amyloid precursor protein cleaving enzyme 1 increases amyloid deposition in brain parenchyma but reduces cerebrovascular amyloid angiopathy in aging BACE x APP[V7171] double-transgenic mice The American Journal of Pathology, 165, (5), pp. 1621-1631.

More information

Published date: 1 November 2004

Identifiers

Local EPrints ID: 55872
URI: http://eprints.soton.ac.uk/id/eprint/55872
ISSN: 0002-9440
PURE UUID: 909f88cd-b207-40ad-ace0-bb4b28ab450c

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Date deposited: 06 Aug 2008
Last modified: 17 Jul 2017 14:31

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Contributors

Author: M. Willem
Author: I. Dewachter
Author: N. Smyth
Author: T. Dooren
Author: P. Borghgraef
Author: C. Haass
Author: F. Leuven

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